Mouse model systems are utilized to study the molecular basis for the pathogenesis of certain retroviruses. The gag-myb-ets-containing ME26 virus causes a high incidence of leukemia in mice. Both in vivo and in vitro, ME26 virus infection leads to the activation in hematopoietic precursor cells of certain erythroid-specific genes, such as GATA-1, Epo receptor, and globin, but not others. Transactivation studies indicate that the ME26 viral gene product transactivates the GATA-1 gene and then cooperates with the GATA-1 protein to transactivate the Epo receptor gene. DNA-binding studies show that the ME26 viral gene product specifically binds to the GATA-1 promoter. Studies utilizing mutated viral genomes suggest that changes in both the myb and ets regions of the virus can alter its biological activity and that both the v-myb and v-ets genes must be expressed as a fusion gene product to have a biological effect. These studies indicate that ME26 virus induces leukemia in mice by a novel mechanism involving the uncoupling of proliferation and differentiation. PVC-211 murine leukemia virus (MuLV) is a neuropathogenic, weaky- leukemogenic variant of the non-neuropathogenic, highly-leukemogenic Friend MuLV. Studies utilizing chimeric viruses indicate that the 5' half of the env gene, which encodes the receptor binding region of the protein, contains the determinant(s) responsible for pathological changes in the central nervous system (CNS). When viruses were tested for their ability to replicate in cultured brain capillary endothelial cells (BCEC), the primary site of PVC-211 MuLV replication within the CNS, there was a direct correlation between the replication efficiency of the virus in BCEC in vitro and its ability to cause neurological disease in vivo. These studies indicate that the sequences in PVC-211 MuLV which render it neuropathogenic affect its replication in BCEC and suggest that efficient viral replication in BCEC is crucial for the pathological changes in the CNS that result in neurological disease.